Liposomes and PLG microparticles as sustained release antitubercular drug carriers—an in vitro–in vivo study
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Objective To study the pharmacokinetics changes of isoniazid and its metablites in rifampicin and isoniazid coadministrated mice.Methods Plasma samples were collected after 10 consecutive days of administration of isoniazid or rifampicin plus isoniazid once a day to mice.Isoniazid and its metablites-acetylhydrazine and hydrazine were determined by liquid chromatography/tandem mass spectrometry.Results Compared with isoniazid group,Ke,Cmax and AUC0-12h of acetylhydrazine increased significantly and t1/2 decreased significantly in rifampicin coadministrated group.AUC0-12h of hydrazine increased by 20% in rifampicin coadministrated group.Conclusion Acetylhydrazine and hydrazine,metabolites of isoniazid,increased significantly when isoniazid was coadministrated with rifampicin,suggesting that the increase of acetylhydrazine concentration plays a role in the hepatotoxicity of isoniazid and rifampicin coadministration.
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The aim of the present study is to formulate and evaluate enteric coated combination tablets of Rifampicin and Isoniazid with improved Rifampicin stability in in-vitro conditions. Rifampicin and Isoniazid were formulated separately as immediate release tablets. Then these tablets were evaluated for the various physical parameters like appearance, weight variation, hardness, friability and disintegration. Then Rifampicin and Isoniazid were mixed and formulated as combination tablets which were enteric coated with Eudragit L-100 using pan coating technique after evaluating them for physical parameters. This is mainly done to prevent isoniazid from interacting with Rifampicin in acidic medium and to improve the stability of Rifampicin. Dissolution studies for the uncoated tablets and enteric coated combination tablets were performed and the cumulative percentage drug release for Rifampicin was calculated. The cumulative percentage drug release for Rifampicin was found to be around 80% when it was taken along with uncoated immediate release Isoniazid tablets for the dissolution study whereas it has been increased to 88% when it is formulated as enteric coated combination tablet. This study proves that Rifampicin interacts with Isoniazid and undergoes degradation to a significant extent in presence of Isoniazid in acidic medium. This interaction and degradation of Rifampicin can be reduced and the stability can be enhanced by preventing the physical contact between these two drugs in the stomach and by making them to release in Intestinal pH.
Fixed-dose combination
Enteric coating
Friability
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Objective: The aim of the present study is to formulate and evaluate enteric coated pellets of Rifampicin and Isoniazid with improved Rifampicin stability in invitro conditions. Methodology: Two different capsule formulations of these drugs were prepared. Formulation-I contains immediate release uncoated pellets of Rifampicin and Isoniazid. Formulation-IIcontains immediate release enteric coated pellets of Rifampicin and Isoniazid. These pellets were evaluated for various physicochemical parameters. Enteric coating was mainly done to prevent the release of these drugs in acidic medium and to improve the stability of Rifampicin by preventing its interaction with Isoniazid in acidic medium. Dissolution studies for both these formulations were performed and the cumulative percentage drug release for Rifampicin was calculated. Results: The cumulative percentage drug release for Rifampicin was found to be around 81% in formulation-I whereas it has been increased to 89% in formulation-II. Conclusion: This study proves that Rifampicin interacts with Isoniazid and undergoes degradation to a significant extent in acidic medium. This interaction and degradation can be reduced and the stabilityof Rifampicin can be enhanced by formulating them as enteric coated dosage forms. Keywords : Rifampicin, Isoniazid, Enteric coating,pellets
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Research on the interaction isoniazid metabolism and rifampicin using rat hepatocytes suspension has been done. As the system metabolism. hepatocytes suspension was prepared by perfusion in the calcium binding media containing EDTA, citrate and glycine was used.
Treatment at the hepatocytes suspension devided into two groups. One group research on the influence of isoniazid on rifampicin metabolism. Second research on the influence of rifampicin on isoniazid metabolism. Each group devided into five subgroups. Result calculated on the base of variation of rifampicin AUC-value beginning from 0 up to 180 minutes showed that isoniazid wilh concentration 5 µg, 10 µg, 15 µg, and 20 µg, did not influence metabolism of rifampicin (10 µg/ml) as showed by no significant changes of AVC values of rifampicin for α= 0.005 on the otherhand result calculated on the based variation of isoniazid AUC-value beginning from 0 up to 180minutes showed that rifampicin with concentration 5 µg, 10 µg, 15 µg, and 20 µg did influence the mctabolism of isoniazid ( 10 µg/ml) as
showed by significant changes of AVC values of isoniazid for α=0.005. Showed that isoniazid mctabolism decrease used as combination of rifampicin
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A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.
Pyrazinamide
Miliary tuberculosis
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The possible existence of kinetic interactions between rifampicin and isoniazid and the effect of the concomitant presence of an impaired liver function were investigated in man. In a first study normal healthy subjects and patients with chronic liver disease received, on three different occasions, a single dose of 600 mg rifampicin or isoniazid and of rifampicin and isoniazid associated in randomized sequences. The results have shown that in both groups the serum levels, half-life values, and urinary excretion of each drug given alone are not significantly different from those observed when the other drug is associated. Serum levels and half-life of rifampicin and isoniazid were significantly higher in patients with chronically impaired liver. In a second study, rifampicin and isoniazid were given in combination at the same doses as in the first study over a period of one week. The results have shown a trend to decrease in the serum levels of rifampicin of the healthy subjects and a trend to increase in the patients with chronic liver disease on day 7 of treatment. In both groups a reduction in the half-life of rifampicin was also observed. No changes in serum isoniazid concentrations were observed between day 1 and day 7 in the healthy subjects, whereas a significant increase was observed in the patients. No significant changes in the half-life of isoniazid were observed.
Liver disease
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Abstract The aim of this study was to establish and validate an alternative high‐performance liquid chromatography method for simultaneous quantification of pyrazinamide, isoniazid, acetyl‐isoniazid and rifampicin in plasma of patients under treatment for tuberculosis. The performed method was lineal ( r 2 > 0.99) in the range of 2.00–50.00 μg/mL for pyrazinamide, 0.50–20.00 μg/mL for both acetyl‐isoniazid and isoniazid, and 1.20–25.00 μg/mL for rifampicin. Precision and trueness were demonstrated with coefficient of variation < 15% and deviations < 15%, respectively, for quality controls samples. The lower limits of quantification were 2.00, 0.50, 0.50, and 1.20 μg/mL for pyrazinamide, isoniazid, acetyl‐isoniazid and rifampicin, respectively. The method was applied for the analysis of plasma from patients with tuberculosis. This method allowed ensuring reliable quantification of the target compounds and their pharmacokinetics parameters. In general, the mean values of maximum concentration of each antituberculosis drug were located within their respective reference therapeutic ranges. However, patients with sub‐therapeutic plasma concentrations of isoniazid and rifampicin were detected. This is the first analytical technique that simultaneously quantifies isoniazid, acetyl‐isoniazid, rifampicin, and pyrazinamide concentrations from plasma samples by high‐performance liquid chromatography with ultraviolet/visible. The proposed method could be applied for therapeutic drug monitoring and pharmacokinetics studies of the four compounds throughout the treatment of tuberculosis patients.
Pyrazinamide
Therapeutic Drug Monitoring
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OBJECTIVE:To investigate the effects of aminosalicylic acid on peak blood concentration of rifampicin in pulmonary tuberculosis patients receiving Isoniazid aminosalicylate tablets.METHODS:Taking the same patients before-after controlled method,observation group received Isoniazid aminosalicylate tablets and Rifampicin capsules,and control group received Isoniazid tablets and Rifampicin capsules.The peak blood concentrations of isoniazid and rifampicin were detected in 2 groups.The effects of Isoniazid aminosalicylate tablets on peak blood concentration of rifampicin were observed.RESULTS:The mean blood concentrations of isoniazid and rifampicin after taking drugs for 1.5 hours were(4.88±2.32)μg·mL-1 and(6.49±3.40)μg·mL-1 in control group,(2.62±2.34)μg·mL-1 and(5.84±2.74)μg·mL-1 in observation group.There was no significant difference in peak blood concentration of rifampicin between two groups(P0.05),and there was significant difference in peak blood concentration of isoniazid between two groups(P0.05).CONCLUSION:Aminosalicylic acid of Isoniazid aminosalicylate tablets has no obvious effect on peak blood concentration of rifampicin.
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